Population pharmacokinetics of intravenous colistin sulfate and dosage optimization in critically ill patients

Yue-Liang Xie; Xin Jin; Shan-Shan Yan; Cui-Fang Wu; Bi-Xiao Xiang; Hui Wang; Wu Liang; Bing-Chang Yang; Xue-Fei Xiao; Zhi-Ling Li; Qi Pei; Xiao-Cong Zuo; Yue Peng

doi:10.3389/fphar.2022.967412

Population pharmacokinetics of intravenous colistin sulfate and dosage optimization in critically ill patients

Front Pharmacol. 2022 Aug 29:13:967412. doi: 10.3389/fphar.2022.967412. eCollection 2022.

Authors

Yue-Liang Xie^{1

2}, Xin Jin³, Shan-Shan Yan³, Cui-Fang Wu^{1

2}, Bi-Xiao Xiang^{1

4}, Hui Wang³, Wu Liang⁵, Bing-Chang Yang³, Xue-Fei Xiao³, Zhi-Ling Li³, Qi Pei^{1

2}, Xiao-Cong Zuo^{1

2}, Yue Peng^{3

6}

Affiliations

¹ Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, China.
² Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of ICU, The Third Xiangya Hospital of Central South University, Changsha, China.
⁴ College of Pharmacy, Zunyi Medical University, Guizhou, China.
⁵ Changsha VALS Technology Co. Ltd., Changsha, China.
⁶ Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, China.

Abstract

Aims: To explore the population pharmacokinetics of colistin sulfate and to optimize the dosing strategy for critically ill patients. Methods: The study enrolled critically ill adult patients who received colistin sulfate intravenously for more than 72 h with at least one measurement of plasma concentration. Colistin concentrations in plasma or urine samples were measured by ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS). The population pharmacokinetics (PPK) model for colistin sulfate was developed using the Phoenix NLME program. Monte Carlo simulation was conducted to evaluate the probability of target attainment (PTA) for optimizing dosing regimens. Results: A total of 98 plasma concentrations from 20 patients were recorded for PPK modeling. The data were adequately described by a two-compartment model with linear elimination. During modeling, creatinine clearance (CrCL) and alanine aminotransferase (ALT) were identified as covariates of the clearance (CL) and volume of peripheral compartment distribution (V2), respectively. In addition, colistin sulfate was predominantly cleared by the nonrenal pathway with a median urinary recovery of 10.05% with large inter-individual variability. Monte Carlo simulations revealed a greater creatinine clearance associated with a higher risk of sub-therapeutic exposure to colistin sulfate. The target PTA (≥90%) of dosage regimens recommended by the label sheet was achievable only in patients infected by pathogens with MIC ≤0.5 mg/L or with renal impairments. Conclusion: Our study showed that the dose of intravenous colistin sulfate was best adjusted by CrCL and ALT. Importantly, the recommended dosing regimen of 1.0-1.5 million units daily was insufficient for patients with normal renal functions (CrCL ≥80 ml/min) or those infected by pathogens with MIC ≥1.0 mg/L. The dosage of colistin sulfate should be adjusted according to renal function and drug exposure.

Keywords: colistin sulfate; critically ill patients; dosing regimens; population pharmacokinetics; urinary recovery.